Science

All Circuits Are Busy

Video Crowd-sourced science has exploded in recent years. An Internet game called Eyewire, from Sebastian Seung’s lab at M.I.T., asks volunteers to trace the fine details of neurons.

May 26, 2014

The Map Makers

By JAMES GORMAN

H. Sebastian Seung is a prophet of the connectome, the wiring diagram of the brain. In a popular book, debates and public talks he has argued that in that wiring lies each person’s identity.

By wiring, Dr. Seung means the connections from one brain cell to another, seen at the level of the electron microscope. For a human, that would be 85 billion brain cells, with up to 10,000 connections for each one. The amount of information in the three-dimensional representation of the whole connectome at that level of detail would equal a zettabyte, a term only recently invented when the amount of digital data accumulating in the world required new words. It equals about a trillion gigabytes, or as one calculation framed it, 75 billion 16-gigabyte iPads.

Dr. Seung, who is in his late 40s and has just left the Massachusetts Institute of Technology for Princeton, is a visionary who projects that this ultimate map of the human brain will be achieved in 20 to 30 years if computer technology continues to progress at its current pace.

He is also a realist. When he speaks publicly, he tells his audiences, “I am my connectome.” But he can be brutally frank about the limitations of neuroscience.

“We’ve failed to answer simple questions,” he said. “People want to know, ‘What is consciousness?’ And they think that neuroscience is up to understanding that. They want us to figure out schizophrenia and we can’t even figure out why this neuron responds to one direction and not the other.”

This mix of intoxicating ideas, and the profound difficulties of testing them, not only defines Dr. Seung’s career but the current state of neuroscience itself. He is one of the stars of the field, and yet his latest achievement, in a paper published this month, is not one that will set the world on fire. He and his M.I.T. colleagues have proposed an explanation of how a nerve cell in the mouse retina — the starburst amacrine cell — detects the direction of motion.

If he’s right, this is significant work. But it may not be what the public expects, and what they have been led to expect, from the current push to study the brain.

At the same time, the scientific work that makes it into the top journals, while deeply serious and perhaps of great significance, is technical and highly specific.

Dr. Seung is adept at conveying a sense of unlimited possibility, of a revolution in technology, of great things to come.

But his alter ego is in the lab, where research on the workings of the starburst amacrine cell better reflect what neuroscientists are trying to understand now.

There is a “huge gap,” Dr. Seung said, between “what the public wants us to know” and “what we actually know.” And in that gap lies the work to be done.

From Theory to the Lab

Dr. Seung started out in physics, as did many other neuroscientists, particularly those interested in theory. He was always interested in the fundamental ideas in science, which meant physics to him, while growing up in Austin, the child of a philosopher and a musician.

A model of one such connection between parts of two neurons in a mouse retina.

Alex Norton / EyeWire

At Harvard, he studied physics as an undergraduate and went on to get his Ph.D. in theoretical physics.

He went to Israel to do postdoctoral research in theoretical neuroscience, and worked at Bell Labs before he went to M.I.T. All the while, even in graduate school, his interest was turning to the deeper puzzles of biology and the mysteries of the brain. Around 2006, Dr. Seung turned his attention to the connectome. “One of the reasons I left physics was that I thought it couldn’t be tested conclusively,” he said. “It seemed like string theory was going to be impossible to test.”

Little did he know, he said, that “neuroscience would be the same.”

“One of the funny things about neuroscience is that it seems like we have so much data and yet we haven’t been able to test theories,” Dr. Seung said. “Theories and speculation can be around for half a century or a century without going beyond, without becoming real science.”

So he switched paths again, turning to experimental work, with the desire to ground theory in the actual, demonstrable workings of the brain. He decided, he said, to “change course and map out real neural networks” — the actual neurons themselves and how they are connected.

Now Dr. Seung is continuing that work at Princeton, commuting, for the time being, from Manhattan, where he lives with his wife and young daughter as they wait for work to be finished on their house.

A Slice of the Brain

What Dr. Seung has concentrated on is not a human brain, not a mouse brain, but the mouse retina. Although the retina is part of the eye, it is also part of the central nervous system. It is composed of brain tissue, with neurons and synapses and, at least for vision, it is where the work of the brain begins, turning mere sensation into perceptions — size, distance, motion.

Winfried Denk, at the Max Planck Institute of Neurobiology, found in 2002 that the starburst amacrine cell was involved in detecting motion. The question was how. To answer that, Dr. Seung analyzed a small bit of connectome from a portion of the retina created by automated electron microscopy. In this process ultrathin slices of brain tissue are scanned by the microscope and the images are put together to form three-dimensional views of tiny chunks of the brain or retina. Jeff Lichtman at Harvard and Dr. Denk have developed such methods, and Dr. Seung has collaborated with both of them.

H. Sebastian Seung projects a complete map of the brain, showing every connection, in 20 to 30 years.

Zach Wise for The New York Times

In the work on the starburst amacrine cell, he analyzed Dr. Denk’s 3-D connectome reconstructions. Part of the work was done by computer and part by humans, including lab technicians. In this case, the public also participated, through an Internet game of sorts that Dr. Seung’s group at M.I.T. developed, called Eyewire. Humans can still do some things better than computers, and one ability they have is pattern recognition. On Eyewire, volunteers examine the models online and trace the fine details of neurons.

Dr. Seung, Jinseop S. Kim, Matthew J. Greene and M.I.T. colleagues analyzed the structure of the starburst amacrine cell and its connections, considering previous work on physiology and the workings of neurons. From that, they proposed a mechanism for how the cell responds to motion in only one direction. It involves two other cells, bipolar cells that are excited by light and send impulses to the starburst cell.

If their analysis is right, the impulses from the bipolar cells have to reach the starburst cell simultaneously in order to make the starburst cell send out its own signal. Although one bipolar cell fires first as an object moves across the mouse’s field of vision, and another fires second, the signal of the first is delayed along the way so that the signals from both bipolar cells arrive at the starburst amacrine cell at the same time. That simultaneous stimulation causes the starburst amacrine cell to send out its own signal, which carries the news that something is moving in a particular direction on to ganglion cells and then to the brain itself. This is a simplified analysis because in reality many pairs of bipolar cells are reporting to any given starburst amacrine cell.

The system is very similar to the motion detection circuit in the fruit fly that Dmitri B. Chklovskii and his colleagues at Janelia Farm reported on last summer. Dr. Chklovskii, who is about to move to the Simons Center for Data Analysis in New York, said of Dr. Seung’s paper, “It validates our results with the fly.” And it raises all sorts of questions about how evolution produced such similar systems in such different animals with such different brains and vision systems, he said.

Calling Dr. Seung’s hypothesis “very bold,” Dr. Chklovskii added: “There’s not much wiggle room there. It’s a very concise model, a very specific mechanism that can be tested with existing tools.” If Dr. Seung is wrong, he will be clearly wrong.

If he is right, then his findings and Dr. Chklovskii’s study are steps toward cracking the code of the brain — exactly how information is coded and travels through circuits of neurons to allow perceptions to be formed, actions to be taken and decisions to be made.

A Drive to Get Data

That is, after all, why Dr. Seung “paused” in his theorizing to be able to put ideas to the test, another bold action. And the adjective is characteristic of his personality as well as his research. He has been called a “rock-star neuroscientist” in the news media, and he takes easily to the stage. In addition to developing Eyewire, he dances and mugs shamelessly for the camera in videos to promote it.

This reconstruction of bipolar cells in a mouse retina, which is composed of brain tissue, and their connections to other neurons reveals the tangle of the central nervous system.

Alex Norton / EyeWire

Eve Marder, at Brandeis, whose work on a specific neural circuit in the crab has changed the understanding of how such circuits work, is a critic of some of the grander ideas of connectomics because, she says, knowing the wiring is never enough on its own, and only in some circumstances is the level of detail in an electron micrograph useful.

But she is an admirer of both Dr. Seung’s theoretical work, and his move to the laboratory to get his hands dirty. “I really respect his decision,” Dr. Marder said, “the fundamental drive to get the data.”

“He is an absolutely outstanding theorist,” said Dr. Tank, who said Dr. Seung could have continued on that path for the rest of his career. Instead he has plunged into the work of trying to corral the vast amount of raw information that comes from techniques like electron microscopy.

“He focuses on what is the bottleneck in the whole process” of connectomics, which is finding a way to turn the vast amount of raw information that comes from electron microscopes into the structure of neurons and their connections, Dr. Tank said.

Dr. Seung, theorist, experimentalist, neuro-evangelist, dancer, debater, is dead serious about his research, but not so much about himself. Talking recently about his disappointment with theoretical science and his current mix of writing, theorizing and experimenting, he laughed.

“I’m worse than a theorist,” he said. “I’m an intellectual.”

Correction: May 31, 2014

An article on Tuesday, about mapping brain cells, misstated when the neuroscientist H. Sebastian Seung started studying theoretical neuroscience. It was in the 1990s, not 2006. The article also referred incorrectly to his child. He has a daughter, not a son. In addition, a picture caption with the article misidentified the elements of a mouse retina that were on display. The picture showed bipolar cells, not a starburst amacrine cell.

The Map Makers: This is the fourth in a series of articles about
new efforts to explore the brain.